EP0326326A1 - Dérivés de la cystéine - Google Patents

Dérivés de la cystéine Download PDF

Info

Publication number: EP0326326A1
Authority: EP; European Patent Office
Prior art keywords: compound; formula; lower alkyl; substituted; cysteine
Prior art date: 1988-01-25
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Granted

Application number

EP89300651A

Other languages

German (de)

English (en)

Other versions

EP0326326B1 (fr

Inventor

Takakazu 302 Kitasakurazuka Park Heim Morita

Shiro Mita

Tadashi Iso

Yoichi Kawashima

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Santen Pharmaceutical Co Ltd

Original Assignee

Santen Pharmaceutical Co Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1988-01-25

Filing date

1989-01-24

Publication date

1989-08-02

1989-01-24 Application filed by Santen Pharmaceutical Co Ltd filed Critical Santen Pharmaceutical Co Ltd

1989-01-24 Priority to AT89300651T priority Critical patent/ATE84303T1/de

1989-08-02 Publication of EP0326326A1 publication Critical patent/EP0326326A1/fr

1993-01-07 Application granted granted Critical

1993-01-07 Publication of EP0326326B1 publication Critical patent/EP0326326B1/fr

2009-01-24 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

150000001944 cysteine derivatives Chemical class 0.000 title abstract description 9
150000001875 compounds Chemical class 0.000 claims abstract description 102
208000019423 liver disease Diseases 0.000 claims abstract description 18
150000003839 salts Chemical class 0.000 claims abstract description 8
125000000217 alkyl group Chemical group 0.000 claims description 22
238000000034 method Methods 0.000 claims description 15
-1 (substituted)phenyl Chemical group 0.000 claims description 14
238000006243 chemical reaction Methods 0.000 claims description 14
239000004201 L-cysteine Substances 0.000 claims description 7
125000002947 alkylene group Chemical group 0.000 claims description 7
239000001257 hydrogen Substances 0.000 claims description 7
229910052739 hydrogen Inorganic materials 0.000 claims description 7
125000001589 carboacyl group Chemical group 0.000 claims description 5
150000002431 hydrogen Chemical class 0.000 claims description 5
NKTHAXRIKIYOIU-YFKPBYRVSA-N (2r)-2-[(2,2-dimethyl-3-sulfanylpropanoyl)amino]-3-sulfanylpropanoic acid Chemical compound SCC(C)(C)C(=O)N[C@@H](CS)C(O)=O NKTHAXRIKIYOIU-YFKPBYRVSA-N 0.000 claims description 4
125000003545 alkoxy group Chemical group 0.000 claims description 4
125000006239 protecting group Chemical group 0.000 claims description 4
208000023275 Autoimmune disease Diseases 0.000 claims description 3
125000003282 alkyl amino group Chemical group 0.000 claims description 3
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
238000006116 polymerization reaction Methods 0.000 claims description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
239000003937 drug carrier Substances 0.000 claims 2
239000008194 pharmaceutical composition Substances 0.000 claims 2
238000004519 manufacturing process Methods 0.000 claims 1
239000002955 immunomodulating agent Substances 0.000 abstract 1
229940121354 immunomodulator Drugs 0.000 abstract 1
230000002584 immunomodulator Effects 0.000 abstract 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
239000000243 solution Substances 0.000 description 43
239000011541 reaction mixture Substances 0.000 description 22
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
229940093499 ethyl acetate Drugs 0.000 description 19
235000019439 ethyl acetate Nutrition 0.000 description 19
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
230000003287 optical effect Effects 0.000 description 15
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
238000001816 cooling Methods 0.000 description 12
239000000203 mixture Substances 0.000 description 12
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 11
239000012044 organic layer Substances 0.000 description 11
238000010898 silica gel chromatography Methods 0.000 description 11
238000012360 testing method Methods 0.000 description 11
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
230000000694 effects Effects 0.000 description 10
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
239000013078 crystal Substances 0.000 description 8
235000011167 hydrochloric acid Nutrition 0.000 description 8
229960000443 hydrochloric acid Drugs 0.000 description 8
230000000144 pharmacologic effect Effects 0.000 description 8
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
VUAFHZCUKUDDBC-BYPYZUCNSA-N Bucillamine Chemical compound CC(C)(S)C(=O)N[C@@H](CS)C(O)=O VUAFHZCUKUDDBC-BYPYZUCNSA-N 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
229960002433 cysteine Drugs 0.000 description 6
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
241000699670 Mus sp. Species 0.000 description 5
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
229910000027 potassium carbonate Inorganic materials 0.000 description 5
210000002966 serum Anatomy 0.000 description 5
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 4
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
241001494479 Pecora Species 0.000 description 4
150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
210000003743 erythrocyte Anatomy 0.000 description 4
238000002474 experimental method Methods 0.000 description 4
239000008101 lactose Substances 0.000 description 4
239000010410 layer Substances 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
241000699666 Mus <mouse, genus> Species 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
239000002775 capsule Substances 0.000 description 3
239000003814 drug Substances 0.000 description 3
229940079593 drug Drugs 0.000 description 3
125000004356 hydroxy functional group Chemical group O* 0.000 description 3
230000002519 immonomodulatory effect Effects 0.000 description 3
210000000987 immune system Anatomy 0.000 description 3
230000001506 immunosuppresive effect Effects 0.000 description 3
235000019359 magnesium stearate Nutrition 0.000 description 3
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
239000000126 substance Substances 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
241000700159 Rattus Species 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
229920001615 Tragacanth Polymers 0.000 description 2
102000003929 Transaminases Human genes 0.000 description 2
108090000340 Transaminases Proteins 0.000 description 2
150000008065 acid anhydrides Chemical class 0.000 description 2
150000001408 amides Chemical class 0.000 description 2
150000003862 amino acid derivatives Chemical class 0.000 description 2
235000019270 ammonium chloride Nutrition 0.000 description 2
239000000305 astragalus gummifer gum Substances 0.000 description 2
210000004027 cell Anatomy 0.000 description 2
239000001913 cellulose Substances 0.000 description 2
229920002678 cellulose Polymers 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
238000009833 condensation Methods 0.000 description 2
230000005494 condensation Effects 0.000 description 2
230000003247 decreasing effect Effects 0.000 description 2
239000002552 dosage form Substances 0.000 description 2
150000002148 esters Chemical class 0.000 description 2
239000000706 filtrate Substances 0.000 description 2
238000009472 formulation Methods 0.000 description 2
239000008187 granular material Substances 0.000 description 2
230000002949 hemolytic effect Effects 0.000 description 2
230000028993 immune response Effects 0.000 description 2
230000036039 immunity Effects 0.000 description 2
238000010348 incorporation Methods 0.000 description 2
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
229920000609 methyl cellulose Polymers 0.000 description 2
239000001923 methylcellulose Substances 0.000 description 2
235000010981 methylcellulose Nutrition 0.000 description 2
238000012986 modification Methods 0.000 description 2
230000004048 modification Effects 0.000 description 2
229910052757 nitrogen Inorganic materials 0.000 description 2
239000000047 product Substances 0.000 description 2
LJPYJRMMPVFEKR-UHFFFAOYSA-N prop-2-ynylurea Chemical compound NC(=O)NCC#C LJPYJRMMPVFEKR-UHFFFAOYSA-N 0.000 description 2
239000011734 sodium Substances 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
210000004989 spleen cell Anatomy 0.000 description 2
NKTHAXRIKIYOIU-RXMQYKEDSA-N (2s)-2-[(2,2-dimethyl-3-sulfanylpropanoyl)amino]-3-sulfanylpropanoic acid Chemical compound SCC(C)(C)C(=O)N[C@H](CS)C(O)=O NKTHAXRIKIYOIU-RXMQYKEDSA-N 0.000 description 1
ACOHBYVUMVZCLF-LJQANCHMSA-N (2s)-3-benzylsulfanyl-2-[(3-benzylsulfanyl-2,2-dimethylpropanoyl)amino]propanoic acid Chemical compound N([C@H](CSCC=1C=CC=CC=1)C(O)=O)C(=O)C(C)(C)CSCC1=CC=CC=C1 ACOHBYVUMVZCLF-LJQANCHMSA-N 0.000 description 1
MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
FLVFEJZAQXYRSV-UHFFFAOYSA-N 2,2-dimethyl-3-methylsulfanylpropanoyl chloride Chemical compound CSCC(C)(C)C(Cl)=O FLVFEJZAQXYRSV-UHFFFAOYSA-N 0.000 description 1
ZHBSGBIQJJSYOP-UHFFFAOYSA-N 2,2-dimethyl-3-sulfanylpropanoic acid Chemical compound SCC(C)(C)C(O)=O ZHBSGBIQJJSYOP-UHFFFAOYSA-N 0.000 description 1
YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
QFPIAXFOSYMMDD-UHFFFAOYSA-N 2-[(2-methyl-2-sulfanylpropanoyl)amino]-4-sulfanylbutanoic acid Chemical compound CC(C)(S)C(=O)NC(C(O)=O)CCS QFPIAXFOSYMMDD-UHFFFAOYSA-N 0.000 description 1
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
JTMBCYAUSCBSEY-UHFFFAOYSA-N 2-methyl-2-sulfanylpropanoic acid Chemical compound CC(C)(S)C(O)=O JTMBCYAUSCBSEY-UHFFFAOYSA-N 0.000 description 1
DXEBUTGNNZLIQM-UHFFFAOYSA-N 3-benzylsulfanyl-2,2-dimethylpropanoyl chloride Chemical compound ClC(=O)C(C)(C)CSCC1=CC=CC=C1 DXEBUTGNNZLIQM-UHFFFAOYSA-N 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
238000011725 BALB/c mouse Methods 0.000 description 1
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
FFFHZYDWPBMWHY-UHFFFAOYSA-N HOMOCYSTEINE Chemical compound OC(=O)C(N)CCS FFFHZYDWPBMWHY-UHFFFAOYSA-N 0.000 description 1
206010035148 Plague Diseases 0.000 description 1
241000700157 Rattus norvegicus Species 0.000 description 1
GHBAYRBVXCRIHT-VIFPVBQESA-N S-benzyl-L-cysteine zwitterion Chemical compound OC(=O)[C@@H](N)CSCC1=CC=CC=C1 GHBAYRBVXCRIHT-VIFPVBQESA-N 0.000 description 1
IDIDJDIHTAOVLG-UHFFFAOYSA-N S-methyl-L-cysteine Natural products CSCC(N)C(O)=O IDIDJDIHTAOVLG-UHFFFAOYSA-N 0.000 description 1
IDIDJDIHTAOVLG-VKHMYHEASA-N S-methylcysteine Chemical compound CSC[C@H](N)C(O)=O IDIDJDIHTAOVLG-VKHMYHEASA-N 0.000 description 1
238000003436 Schotten-Baumann reaction Methods 0.000 description 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
230000007059 acute toxicity Effects 0.000 description 1
231100000403 acute toxicity Toxicity 0.000 description 1
150000001412 amines Chemical class 0.000 description 1
229910021529 ammonia Inorganic materials 0.000 description 1
235000011114 ammonium hydroxide Nutrition 0.000 description 1
150000003863 ammonium salts Chemical class 0.000 description 1
125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
159000000007 calcium salts Chemical class 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
150000001721 carbon Chemical group 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
231100000749 chronicity Toxicity 0.000 description 1
230000000052 comparative effect Effects 0.000 description 1
WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 1
238000011161 development Methods 0.000 description 1
150000005332 diethylamines Chemical class 0.000 description 1
XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
239000003889 eye drop Substances 0.000 description 1
229940012356 eye drops Drugs 0.000 description 1
229910052736 halogen Inorganic materials 0.000 description 1
150000002367 halogens Chemical class 0.000 description 1
125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
229940018158 hydroxypropylcellulose 5 mg Drugs 0.000 description 1
230000003053 immunization Effects 0.000 description 1
238000002649 immunization Methods 0.000 description 1
238000009169 immunotherapy Methods 0.000 description 1
239000000411 inducer Substances 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
150000007529 inorganic bases Chemical class 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
239000011630 iodine Substances 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
210000004185 liver Anatomy 0.000 description 1
159000000003 magnesium salts Chemical class 0.000 description 1
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
239000000178 monomer Substances 0.000 description 1
FRCDQZGAGKQZBE-LURJTMIESA-N n-[(2r)-1-(dimethylamino)-1-oxo-3-sulfanylpropan-2-yl]-2-methyl-2-sulfanylpropanamide Chemical compound CN(C)C(=O)[C@H](CS)NC(=O)C(C)(C)S FRCDQZGAGKQZBE-LURJTMIESA-N 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
239000000843 powder Substances 0.000 description 1
238000002360 preparation method Methods 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
238000011552 rat model Methods 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
206010039073 rheumatoid arthritis Diseases 0.000 description 1
MUMBYGUCSJAOSA-UHFFFAOYSA-N s-(3-chloro-2,2-dimethyl-3-oxopropyl) benzenecarbothioate Chemical compound ClC(=O)C(C)(C)CSC(=O)C1=CC=CC=C1 MUMBYGUCSJAOSA-UHFFFAOYSA-N 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
239000012258 stirred mixture Substances 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
239000000829 suppository Substances 0.000 description 1
230000001629 suppression Effects 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
239000003826 tablet Substances 0.000 description 1
125000003396 thiol group Chemical group [H]S* 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
231100000820 toxicity test Toxicity 0.000 description 1
JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group

Definitions

This invention relates to cysteine derivatives of the formula[I] and salts thereof, wherein R1 is lower alkyl; R2 is lower alkyl; R3 and R4 are the same or different hydrogen, lower alkyl,lower alkanoyl, (substituted)phenyl lower alkyl, (substituted)phenylcarbonyl, furoyl or thenoyl; R5 is hydroxy, lower alkoxy, amino or lower alkylamino; A is straight or branched lower alkylene; m is 0 or 1; n is 1 or 2 with the proviso that when m is 0, n is 1 and R5 is hydroxy, at least either the R3 or R4 is (substituted)phenyl lower alkyl, (substituted)phenylcarbonyl, furoyl or thenoyl; and when n is 2, R4 should not be lower alkyl.
R1 is lower alkyl
R2 is lower alkyl
lower alkyl intends to designate straight or branched C1 - C6 lower alkyl exemplified by methyl, ethyl, propyl, isopropyl and hexyl.
lower alkanoyl intends to designate straight or branched C1 - C6 lower alkanoyl exemplified by acetyl, propionyl, pivaloyl and hexanoyl.
(substituted) in (substituted)phenyl lower alkyl and (substituted)phenylcarbonyl intends to designate that phenyl nucleus thereof can be substituted by lower alkyl, lower alkoxy or halogen.
cysteine derivatives are known to have many kinds of efficacy such as suppression of liver disorders and anti-rheumatism. But, there are very few studies which reported the influence on pharmacological efficacy by incorporation of alkylene group in the side chain of cysteine derivatives, expansion of the alkylene length of the side chain or by substitution of radicals. So, we studied cysteine derivatives in more detail.
the compounds of the formula[I] can be prepared by the similar methods shown in US Patents 4305958 and 4255446 or Japanese Patents Publication 12119/1984.
the compound of the formula[I] can be prepared by the reaction of amino acid derivative of the formula[II] with carboxylic acid derivative of the formula[III] or active derivative thereof.
Active derivative defined above is reactive derivative of carboxylic acid exemplified by acid chloride, acid anhydride and mixed acid anhydride. Active derivative of the compound the formula [III] can be converted into the compound of the formula[I] by the usual method such as Schotten-Baumann method which is generally used for condensation of amine derivative with carboxylic acid derivative.
Carboxylic acid of the formula [III] can be converted directly into the compound of the formula [I] using a condensing agent such as N,N′-dicyclohexylcarbodiimide(DCC).
a condensing agent such as N,N′-dicyclohexylcarbodiimide(DCC).
reaction condition such as temperature or reaction time.
the compound of the formula[I] can be prepared by the reaction of amino acid derivative of the formula [II] with polythioester of the formula[IV], wherein l is a polymerization degree having a mean molecule weight of about 200-1500.
the compound of the formula[IV] can be prepared from the corresponding monomer of the formula[V] using a condensing agent such as DCC in an organic solvent.
reaction is usually performed in a presence of base such as sodium carbonate or potassium carbonate.
the compound of the formula[I] can be converted into pharmaceutically acceptable salts of inorganic or organic base.
salts examples include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, diethylamine salt and triethanolamine salt.
the compounds of this invention have stereoisomers because of the existence of one or more asymmetric carbon atom, and these isomers are included in this invention.
a liver disorder model caused by an administration of CCl4 to a rat is widely used to examine efficacy of a compound on liver diseases.
GOT and GPT values in the serum are used as an indication of a degree of liver disorder. If the value, which is raised by liver disorder, falls by an administration of a compound, the compound is judged effective on liver dosorder.
This experimental method is to examine the efficacy on the immune system according to increase or decrease of the number of haemolytic plague-forming cells of mouse spleen cells. As shown in the pharmacological test, the compound of this invention shows an excellent immunosuppressive effect.
the compound of this invention shows more effect than the compound described in the US Patent.
the compound of this invention must be a new type of drug for liver diseases because the compound decreased the value of GOT and GPT in serum and suppressed the immunity.
the compound of this invention can be used as a drug for autoimmune diseases such as rheumatoid arthritis.
the compound(s) of this invention can be administered either orally or parenterally.
dosage forms are tablet, capsule, powder, granule, suppository, injection, eye drops and percutaneous.
the dosage is adjusted depending on symptom, dosage form, etc., but usual daily dosage is 1 to 5000mg in one or a few divided doses.
DMF solution of polythioester was prepared using 3-mercaptopivalic acid(40.3g) and N,N′-dicyclohexylcarbodiimide (61.9g) by the similar method as Example 1.
N-(2,2-Dimethyl-3-mercaptopropionyl)-L-cysteine(23.7g) was dissolved in a solution of potassium carbonate(41.5g) in water (150ml) under ice-cooling. To this solution, methyl iodide (36.9g) was added. After the addition, the reaction mixture was stirred for 30 minutes under ice-cooling and for 1 hour at room temperature. To the reaction mixture, 1 N iodine solution(15ml) was added and the solution was washed with ethyl acetate. The aqueous layer was acidified with 6 N hydrochloric acid and extracted with ethyl acetate.
capsules which contains 10mg, 30mg, 50mg or 100mg of the compound No.2, were prepared.
Granule compound No.2 50mg lactose 54mg crystalline cellulose 20mg polyvinylpyrrolidone K-30 5mg magnesium stearate 1mg 130mg
the rat liver disorder model cause by CCl4 is generally used to examine the efficacy of a drug for liver diseases.
test compound was suspended in tragacanth gum solution and administered orally to male Wistar rats ( 5rats a group) at a dose of 300mg/kg.
CCl4 a liver disorder inducer, was given intraperitoneally at a dose of 0.25ml/kg.
test compound suspended in 1% methyl cellulose solution was administered continuously for 4 days.
mice were killed and the number of haemolytic plaque-forming spleen cells were measured.
the compound of this invention shows excellent immunosuppressive effect and its effect is more potent than that of the known compound.
the compound No.2 was suspended in 0.5% methyl cellulose solution at 20% concentration.
the solution was administered orally to ddY mice ( male, 5 weeks age, 6 mice a group ) at a dose of 2000mg/kg.
Toxicity of the compound No.2 was weak with a single case of death.
LD50 was over 2000 mg/kg.

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Epidemiology (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

EP89300651A 1988-01-25 1989-01-24 Dérivés de la cystéine Expired - Lifetime EP0326326B1 (fr)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
AT89300651T ATE84303T1 (de)	1988-01-25	1989-01-24	Cysteinderivate.

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
JP1418988		1988-01-25
JP14189/88		1988-01-25

Publications (2)

Publication Number	Publication Date
EP0326326A1 true EP0326326A1 (fr)	1989-08-02
EP0326326B1 EP0326326B1 (fr)	1993-01-07

Family

ID=11854177

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP89300651A Expired - Lifetime EP0326326B1 (fr)	1988-01-25	1989-01-24	Dérivés de la cystéine

Country Status (7)

Country	Link
EP (1)	EP0326326B1 (fr)
KR (1)	KR890011835A (fr)
CN (1)	CN1036201A (fr)
AT (1)	ATE84303T1 (fr)
CA (1)	CA1336979C (fr)
DE (3)	DE68904203T4 (fr)
ES (1)	ES2012958A6 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0455833A4 (en) *	1989-11-27	1993-06-09	Santen Pharmaceutical Co., Ltd.	Amino acid derivative
EP0639566A4 (fr) *	1991-01-10	1994-07-05	Santen Pharmaceutical Co Ltd	Compose cyclique.
WO2002013814A1 (fr) *	2000-08-11	2002-02-21	The Lawson Health Research Institute	Compositions enrayant un dysfonctionnement des ilots de langerhans ainsi que des maladies auto-immune et methodes afferentes
US7875268B2 (en)	2004-04-06	2011-01-25	L'oreal S.A.	Dimercaptoamides, compositions comprising them as reducing agents, and processes for permanently reshaping keratin fibers therewith
US8188119B2 (en)	2008-10-24	2012-05-29	Eisai R&D Management Co., Ltd	Pyridine derivatives substituted with heterocyclic ring and γ-glutamylamino group, and antifungal agents containing same

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6166072A (en) *	1998-08-03	2000-12-26	Allelix Neuroscience, Inc.	Amino acid derivatives

Citations (4)

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Publication number	Priority date	Publication date	Assignee	Title
GB1530071A (en) *	1976-03-08	1978-10-25	Santen Pharmaceutical Co Ltd	Cysteine derivatives
US4241086A (en) *	1978-10-11	1980-12-23	Santen Pharmaceutical Co., Ltd.	Method for treating rheumatism
US4255446A (en) *	1978-10-11	1981-03-10	Santen Pharmaceutical Co. Ltd.	Cysteine derivatives
GB2096145A (en) *	1980-09-20	1982-10-13	Santen Pharmaceutical Co Ltd	Disulfide type cysteine derivatives

1989
- 1989-01-24 CA CA000588980A patent/CA1336979C/fr not_active Expired - Fee Related
- 1989-01-24 DE DE89300651T patent/DE68904203T4/de not_active Expired - Lifetime
- 1989-01-24 ES ES898900232A patent/ES2012958A6/es not_active Expired - Lifetime
- 1989-01-24 DE DE198989300651T patent/DE326326T1/de active Pending
- 1989-01-24 AT AT89300651T patent/ATE84303T1/de not_active IP Right Cessation
- 1989-01-24 EP EP89300651A patent/EP0326326B1/fr not_active Expired - Lifetime
- 1989-01-24 DE DE8989300651A patent/DE68904203D1/de not_active Expired - Fee Related
- 1989-01-25 KR KR1019890000768A patent/KR890011835A/ko not_active Ceased
- 1989-01-25 CN CN89101543A patent/CN1036201A/zh active Pending

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB1530071A (en) *	1976-03-08	1978-10-25	Santen Pharmaceutical Co Ltd	Cysteine derivatives
US4305958A (en) *	1976-03-08	1981-12-15	Santen Pharmaceutical Co., Ltd.	Cysteine derivatives
US4241086A (en) *	1978-10-11	1980-12-23	Santen Pharmaceutical Co., Ltd.	Method for treating rheumatism
US4255446A (en) *	1978-10-11	1981-03-10	Santen Pharmaceutical Co. Ltd.	Cysteine derivatives
GB2096145A (en) *	1980-09-20	1982-10-13	Santen Pharmaceutical Co Ltd	Disulfide type cysteine derivatives

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0455833A4 (en) *	1989-11-27	1993-06-09	Santen Pharmaceutical Co., Ltd.	Amino acid derivative
EP0639566A4 (fr) *	1991-01-10	1994-07-05	Santen Pharmaceutical Co Ltd	Compose cyclique.
WO2002013814A1 (fr) *	2000-08-11	2002-02-21	The Lawson Health Research Institute	Compositions enrayant un dysfonctionnement des ilots de langerhans ainsi que des maladies auto-immune et methodes afferentes
WO2002013813A1 (fr) *	2000-08-11	2002-02-21	The Lawson Health Research Institute	Inhibition du dysfonctionnement des îlots de langerhans et de troubles autoimmunes, et compositions à cet effet
US7875268B2 (en)	2004-04-06	2011-01-25	L'oreal S.A.	Dimercaptoamides, compositions comprising them as reducing agents, and processes for permanently reshaping keratin fibers therewith
US8188119B2 (en)	2008-10-24	2012-05-29	Eisai R&D Management Co., Ltd	Pyridine derivatives substituted with heterocyclic ring and γ-glutamylamino group, and antifungal agents containing same

Also Published As

Publication number	Publication date
ATE84303T1 (de)	1993-01-15
DE68904203T2 (de)	1993-05-13
DE326326T1 (de)	1990-02-08
ES2012958A6 (es)	1990-04-16
CA1336979C (fr)	1995-09-12
DE68904203D1 (de)	1993-02-18
KR890011835A (ko)	1989-08-22
DE68904203T4 (de)	1993-10-28
CN1036201A (zh)	1989-10-11
EP0326326B1 (fr)	1993-01-07

Publication	Publication Date	Title
US5284872A (en)	1994-02-08	Nitrato alkanoic acid derivatives, methods for their production, pharmaceutical compositions containing the derivatives and medicinal uses thereof
US4440788A (en)	1984-04-03	Cysteine derivatives
EP0613883A1 (fr)	1994-09-07	Derive d'acide hydroxamique
US4418075A (en)	1983-11-29	Epoxysuccinyl amino acid derivatives
US5254579A (en)	1993-10-19	N-(5-thioxo-L-prolyl)-L-cysteine, derivatives thereof, processes for the preparation thereof and pharmaceutical compositions containing them
EP0326326A1 (fr)	1989-08-02	Dérivés de la cystéine
US5082836A (en)	1992-01-21	Compositions and methods of use of cyclic sulfur-containing compounds
US4322436A (en)	1982-03-30	Novel substituted phenylacetic acid amide compounds
US5292926A (en)	1994-03-08	Cysteine derivatives
US4250192A (en)	1981-02-10	Novel substituted phenylacetic acid amide compounds
US4421765A (en)	1983-12-20	Substituted phenylacetic acid amide compounds
EP0103320A2 (fr)	1984-03-21	Thioesters de l'acide acétylsalicylique, un procédé de préparation, et compositions pharmaceutiques les contenant
US4775676A (en)	1988-10-04	Thiazolidine derivatives, process for their preparation and pharmaceutical compositions
HRP920948A2 (en)	1997-10-31	Nitratoalkanecarbone acid derivatives, process for the preparation thereof, the use of the same and drugs containing them
EP0301474B1 (fr)	1993-09-29	Dérivés de cystéine doués d'une activité expectorante
JPH0686419B2 (ja)	1994-11-02	システイン関連化合物
US4474800A (en)	1984-10-02	Epoxysuccinyl amino acid derivatives
KR850001880B1 (ko)	1985-12-28	트란스-4-[n-(3', 4'-메틸렌디옥시벤질리덴)아미노메틸] 사이클로헥산-1-카복실산 및 이의 유도체의 제조방법
EP0051682B1 (fr)	1984-09-05	Derives de la cysteine et procede pour leur preparation
JPH0684362B2 (ja)	1994-10-26	環状含硫黄化合物
US4916130A (en)	1990-04-10	Platelet agglutination-inhibiting agent
EP1047668B1 (fr)	2003-05-21	Triazepinones, procede pour leur preparation et leur application therapeutique
JP2717317B2 (ja)	1998-02-18	Ｎ―アシルーチアゾリジン―２―チオン誘導体
WO1991013883A1 (fr)	1991-09-19	Derive de l'acide thiolactique-(thenoyle-2)-s presentant une activite pharmacologique
NL8104049A (nl)	1982-01-04	Werkwijze ter bereiding van een therapeutisch preparaat, alsmede werkwijze ter bereiding van daarvoor geschikte verbindingen.

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